美国芝加哥大学Marcus R. Clark和Malay Mandal共同合作，近期取得重要工作进展。他们研究发现，BRWD1通过将静态黏连蛋白转化为动态黏连蛋白来协调小前b细胞染色质拓扑结构。相关研究成果2023年11月20日在线发表于《自然—免疫学》杂志上。

据介绍，淋巴细胞的发育包括增殖选择和抗原受体基因重组的顺序和相互排斥的细胞状态。每种状态之间的转换都需要表观遗传学和转录程序的大规模协调变化。目前尚不清楚这种情况是如何发生的。

研究人员证明了在小前B细胞中，谱系和阶段特异性表观遗传读取器溴结构域和WD重复序列包含蛋白1（BRWD1）重新排列三维染色质拓扑结构以影响增殖和基因重组分子程序之间的转换。BRWD1调节与启动子相互作用的平衡增强子和活跃增强子之间的转换，并与Igk位点收缩协调这种转换。BRWD1通过将染色质结合的静态黏连蛋白转化为动态黏连蛋白来介导长程环。ATP耗竭显示黏连蛋白转化是决定染色质动态循环的主要能量机制。

总之，这一发现提供了一种新的黏连蛋白调节机制，并揭示了黏连蛋白的功能如何由谱系背景机制决定，以促进特定的细胞命运转变。

附：英文原文

Title: BRWD1 orchestrates small pre-Bcell chromatin topology by converting static to dynamic cohesin

Author: Mandal, Malay, Maienschein-Cline, Mark, Hu, Yeguang, Mohsin, Azam, Veselits, Margaret L., Wright, Nathaniel E., Okoreeh, Michael K., Yoon, Young me, Veselits, Jacob, Georgopoulos, Katia, Clark, Marcus R.

Issue&Volume: 2023-11-20

Abstract: Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Here we demonstrate that in small pre-Bcells, the lineage and stage-specific epigenetic reader bromodomain and WD repeat-containing protein 1 (BRWD1) reorders three-dimensional chromatin topology to affect the transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters, and coordinated this switch with Igk locus contraction. BRWD1 did so by converting chromatin-bound static to dynamic cohesin competent to mediate long-range looping. ATP-depletion revealed cohesin conversion to be the main energetic mechanism dictating dynamic chromatin looping. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be dictated by lineage contextual mechanisms to facilitate specific cell fate transitions.

DOI: 10.1038/s41590-023-01666-z

Source: https://www.nature.com/articles/s41590-023-01666-z